Early Life Stress Induced Mechanisms of Cardiovascular Disease Risk and Resilience

生命早期压力诱发心血管疾病风险和恢复力的机制

• 批准号: 10555121
• 负责人: Jennifer S Pollock
• 金额: $ 224.27万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555121
• 关键词: Address; Adolescence; Adolescent; Adult; Animal Model; Basic Science; Bioinformatics; Biometry; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Central Nervous System; Child; Child Rearing; Clinic; Clinical; Collaborations; Data; Data Analytics; Diastolic blood pressure; Diet; Economics; Elderly; Endothelium; Ensure; Europe; Exposure to; Functional disorder; Future; Goals; Grant; Health; Healthcare; Heart Rate; Household; Human; Hypertension; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Life; Life Stress; Macrophage; Manuscripts; Measurement; Mediating; Mentors; Mission; Molecular; National Heart, Lung, and Blood Institute; North America; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Physical activity; Physiologic pulse; Prevention; Prevention strategy; Program Research Project Grants; Psychological Stress; Publications; Recording of previous events; Reproducibility; Risk; Risk Factors; Rodent; Rodent Model; Sampling; Sexual abuse; Specimen; Stressful Event; Structure; System; Techniques; Technology; Telemetry; Temperature; Translating; Translations; Vascular Diseases; Vascular Endothelium; Vascular resistance; Work; abuse neglect; blood pressure control; cardiovascular disorder risk; care burden; circadian; clinically relevant; cost; data management; disorder risk; early life stress; effective therapy; emerging adult; epigenome; experience; gut microbiome; immune activation; insight; lifestyle factors; metabolome; monocyte; multiple omics; neural network; novel; physical abuse; programs; prospective; protective factors; resilience; stressor; synergism; transcriptome; translational potential; translational study; traumatic event; violence exposure

OVERALL SUMMARY Early life stress (ELS) is defined as stressful and traumatic events, such as household dysfunction, neglect, sexual or physical abuse, economic hardship, and exposure to violence, experienced up to 18 years. ELS was identified as a cardiovascular disease (CVD) risk factor over 20 years ago, but mechanistic insights into its effects remain very limited. Exposure to ELS is pervasive in the US with ~50% of children and adolescents having one or more major ELS experiences. ELS exposure increases the risk traditional CVD risk factors - by the 3rd-4th decade of life. A recent analysis of healthcare burden in Europe and North America attributed $748 billion in annual costs to the effects of ELS, with 75% of those costs in people with multiple ELS exposures. The significance of our work aligns with the NHLBI mission to promote the prevention and treatment of cardiovascular diseases enhancing the health of all individuals to live longer and fulfilling lives. Among individuals with a history of ELS exposure, vascular dysfunction (elevated peripheral vascular resistance, increased vascular stiffness) and elevated diastolic blood pressure are already evident in early adulthood. The overall goal of our program project grant (PPG) is to define mechanisms by which ELS leads to CVD risk and inform strategies for prevention and effective treatment of CVD consequences in individuals exposed to ELS. This PPG will address two critical barriers to fulfill our goal: 1) Need for ELS-specific in-depth mechanistic and translational studies; and, 2) Identify modifiable protective factors that can reduce ELS-induced CVD risk. The overarching hypothesis of our PPG is that ELS induces immune cell activation leading to vascular dysfunction with increased hypertension risk and CVD risk that are exacerbated by later life stressors or moderated by resilience/protective factors. This PPG with both basic science and clinical projects utilizes a synergistic and integrative approach translating concepts from clinically relevant rodent models to humans. Our group is extremely synergistic, with each leader bringing unique expertise from different scientific backgrounds focused on our overall goal to understand mechanisms of ELS induced indicators of CVD risk and resilience. Over the past several years, our team built strong collaborations translating discoveries between basic and clinical labs with several pilot grants, co-mentoring trainees, and multiple jointly authored abstracts, manuscripts, and publications. The four projects and three cores are integrated in their goals and impact such that much more will be achieved together than separately. This PPG utilizes a range of approaches to investigate in-depth molecular mechanisms of ELS-induced hypertension and vascular disease risk as well as to delineate protective factors mediating resiliency to this risk. The results will have important translational potential pointing to new intervention or prevention strategies for the health consequences of CVD and reducing the healthcare burden of CVD.

总结 早期的生活压力（EL）被定义为压力和创伤性事件，例如家庭功能障碍，忽视， 性或身体虐待，经济困难以及暴力暴露，最多18年。 Els是 在20年前被确定为心血管疾病（CVD）危险因素 保持非常有限。在美国，暴露于ELS是普遍的，约有50％的儿童和青少年有一个 或更多主要的EL经验。 ELS暴露增加了传统CVD风险因素的风险 - 到第3-4 生命十年。最近对欧洲和北美医疗保健负担的分析归因于7480亿美元 ELS影响的年成本，其中75％的费用在多个EL暴露的人中。这 我们工作的意义与NHLBI的任务一致，以促进心血管的预防和治疗 疾病增强了所有人的健康状况，使生活更长和实现生活。有历史的人 EL暴露，血管功能障碍（外周血管阻力升高，血管僵硬增加） 在成年初期，舒张压升高已经显现出来。我们计划的总体目标 项目赠款（PPG）是定义ELS导致CVD风险并告知预防策略的机制 并有效地治疗了暴露于ELS的个体中CVD后果。该PPG将解决两个关键 实现我们的目标的障碍：1）需要特定于ELS的深入机理和翻译研究；以及，2）识别 可修改的保护因素可以降低ELS引起的CVD风险。我们PPG的总体假设是 ELS诱导免疫细胞激活，导致血管功能障碍，高血压风险增加和 CVD风险因以后的生命压力源加剧或弹性/保护因素而加剧。此PPG与 基础科学和临床项目都采用了一种协同和综合方法，转化了 临床上相关的啮齿动物模型。我们的小组非常协同，每个领导者都带来了独特的 来自不同科学背景的专业知识集中于我们了解ELS机制的整体目标 引起的CVD风险和弹性指标。在过去的几年中，我们的团队建立了强大的合作 通过几个飞行员赠款，会计学员以及 多个共同撰写的摘要，手稿和出版物。四个项目和三个核心是 整合其目标和影响，使得共同实现更多的实现。这个ppg 利用一系列方法来研究ELS诱导的高血压和 血管疾病风险以及描述介导这种风险弹性的保护因素。结果将 具有重要的翻译潜力，指向健康的新干预或预防策略 CVD的后果和减轻CVD的医疗保健负担。